Abstract
Her2/neu regulates angiogenesis in human breast cancer, in part by stabilizing hypoxia-inducible factor 1alpha (HIF-1alpha), causing accumulation of the HIF-1 heterodimer and thus increasing expression of the proangiogenic cytokine VEGF. Her2/neu has recently been shown to be overexpressed in a subset of Wilms tumors. Using her2/neu (+) and her2/neu (-) Wilms tumor cell lines, we tested the effect of blocking anti-her2/neu antibody in vitro and in vivo. Blocking antibody did not alter VEGF expression in vitro, but decreased expression of VEGF in her2/neu (+) Wilms tumor xenografts. Tumor suppression was less marked than in parallel experiments using agents directly blocking VEGF. HIF-1alpha immunostaining was not altered in her2/neu (+) xenografts exposed to blocking antibody. These results suggest that her2/neu contributes to Wilms tumor angiogenesis in vivo by regulating VEGF, but other processes may act to rescue HIF-1alpha and thus to support tumor growth in this system.
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal, Humanized
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Cell Division
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Cell Line, Tumor
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DNA-Binding Proteins / biosynthesis*
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Dose-Response Relationship, Drug
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Down-Regulation
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Female
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immunohistochemistry
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In Situ Hybridization
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In Situ Nick-End Labeling
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Mice
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Mice, Nude
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Microscopy, Fluorescence
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Neoplasm Transplantation
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Neoplasms, Experimental / metabolism*
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Neovascularization, Pathologic
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Nuclear Proteins / biosynthesis*
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-2 / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors*
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Trastuzumab
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Vascular Endothelial Growth Factor A / biosynthesis*
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Wilms Tumor / metabolism*
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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DNA-Binding Proteins
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Receptor, ErbB-2
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Trastuzumab